Administrative Supplement P30 Cancer Center Support Grant (CCSG): Phase 1 Study of Olaparib in Combination with Durvalumab (MEDI4736) and Concurrent Radiation Therapy Following First-Line Chemotherapy

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Abstract The P30 ETCTN Leadership Supplement is requested to support the oversight and conduct of the investigator- initiated phase 1 clinical trial NCI10464 “Phase 1 Study of Olaparib in Combination with Durvalumab (MEDI4736) and Concurrent Radiation Therapy Following First-Line Chemotherapy in Locally Advanced Unresectable Pancreatic Cancer”. Dr. Michael Green and Dr. Vaibhav Sahai are serving as the study principal investigators and University of Michigan is the lead academic site. The study was approved by the NCI and opened to academic participating sites through the ETCTN in November 2022. The first subject enrollment occurred in May 2023. Our central hypothesis is that the combination of radiotherapy and PARP inhibition via olaparib will elicit anti-tumor immune responses and sensitize patients to immune checkpoint blockade. The major premise for this study is based upon the ability of PARP inhibitors when given in combination with radiation to induce DNA damage and replication stress that induce PRR signaling and a T1IFN-mediated innate immune response. T1IFN has broad immune consequences including antigen presentation, chemokine production, promotion of CD8+ T-cell cytotoxic activity, and induction of PD-L1 expression. On this basis, we hypothesize that combined therapy with PARP inhibitor, radiation, and PD-L1-targeting immunotherapy will increase local as well as systemic tumor responses mediated by adaptive immunity. The potential for this therapeutic strategy to induce both local and systemic immune responses is highly relevant in LAPC given the presence of micrometastatic disease in most of these patients as well as the critical need to control the local tumor to ultimately cure the cancer. The trial uses time-to-event continual reassessment methodology (TiTE- CRM) design to find the maximum tolerated dose (MTD) of olaparib in combination with durvalumab and radiation which allows information from all patients treated (even those with only partial observation) to contribute information for calculating the dose-toxicity relationship. The trial seeks to estimate the MTD level across 18 patients with estimated dose limiting toxicity probability closest to 25%, but no greater than 27.5%, during the observation period of 42 days starting with radiotherapy. Safety and efficacy along with endpoints of preliminary efficacy estimates, including objective response rate, progression-free survival and overall survival will be reported. Pre-treatment tissue and serial blood will be obtained to examine the effect of baseline immune and genetic markers as well as on-target effects.